Half of all Americans either have or are at serious risk for developing osteoporosis. Bone mineral density (BMD) can be readily measured in a clinical setting, and low BMD is associated with increased risk of osteoporotic fracture. Cardiovascular disease (CVD) is a major cause of death in industrialized societies, and it is well established that raising HDL cholesterol reduces the risk of cardiovascular disease. Studies have shown that low BMD can be used as an independent predictor of CVD, and patients with CVD are more likely to have low BMD. Smoking, lack of exercise and eating a high fat Western diet increases the risk of developing both CVD and osteoporosis. Together these suggest that there may be shared causes for these two diseases. Both BMD and serum HDL levels have been shown to be genetically regulated. Preliminary studies in humans have suggested the existence of shared genetic causes for both of these phenotypes, but, as environmental and lifestyle factors influence both BMD and serum HDL levels, identifying the genetic link between CVD and osteoporosis has been difficult. The mouse is an excellent model for mapping genes that underlie complex traits, and, unlike in human studies, environment can be controlled and modulated as needed in studies using the mouse. Two quantitative trait loci (QTL) for BMD have been identified on mouse Chromosome 1 and 8 that are coincident for QTL for serum HDL. Furthermore, both of these BMD QTL interact with dietary cholesterol intake. The Chr 1 QTL has been narrowed down to one gene, and the Chr 8 QTL has been narrowed down to 4 candidate genes. In this application, a knockout mouse for the candidate gene on Chr 1 will be developed to confirm that: 1) this gene underlies the BMD QTL on Chr 1; 2) this QTL interacts with dietary cholesterol intake to affect BMD; and 3) this same gene regulates serum HDL levels. In the second Aim, the gene underlying the BMD QTL on Chr 8 will be identified, and the hypothesis that a single gene at this locus regulates both the BMD and HDL QTL will be confirmed. PUBLIC HEALTH RELEVANCE: Low bone mineral density (BMD) is associated with increased risk of osteoporotic fracture, and low levels of HDL cholesterol are associated with increased risk for heart disease. This research will help us better comprehend and identify the genes that simultaneously regulate BMD and HDL cholesterol levels. Understanding the shared genetic causes of heart disease and osteoporosis will lead to new and better treatments and improve our ability to screen for and prevent these common and debilitating diseases.